PTP1b Inhibition Restores the Innate Anti-tumor Response During Chemotherapy

项目总结 尽管在诊断和治疗方面取得了进步，但癌症仍是美国第二大死因 各州。适应性免疫检查点(如PD-1和CTLA4)的发现和定位一直是一个福音 给癌症患者。不幸的是，只有一小部分患者会有反应，而那些有反应的患者往往会复发。在一个 为了提高适应性免疫靶向治疗的疗效，已经提出了几项临床试验 或正在探索将检查站封锁与化疗相结合。一个理由是 联合疗法是化疗诱导免疫原性肿瘤细胞死亡，这提供了强有力的 通过释放新抗原和损伤相关分子模式激活抗肿瘤反应 (抑制)启动先天的促炎反应。 我们发现并表征了一种新的天然免疫检查点，肿瘤细胞利用它来抑制 化疗期间的免疫反应。我们发现，肿瘤分泌蛋白结合并激活 巨噬细胞Mer受体，导致关键的Toll样受体(TLR)适配器表达减少 MyD88蛋白。在没有MyD88的情况下，巨噬细胞不再能够对DAMP/TLR信号做出反应， 有效预防化疗期间的促炎反应。这种抑制机制是 以各种来源的肿瘤为特征，包括黑色素瘤、肺癌、胰腺癌和乳腺癌。 我们的机制研究证实，配体激活的巨噬细胞Mer可诱导三元复合体 形成，增加Mer、STAT1和一种名为PTP1B的磷酸酶的联系。这个建筑群 减少STAT1的磷酸化和核转位，导致MyD88减少 表情。用PTP1B抑制剂治疗可阻断这一免疫抑制过程，并恢复受潮 介导的体外和体内激活。PTP1B抑制与化疗联合导致约50% 在包括化疗耐药模型在内的多种小鼠癌症中，肿瘤生长减少。 我们假设通过靶向Mer：PTP1B轴，我们可能能够改善先天的，并且 化疗期间随后的适应性、免疫反应。为了检验我们的假设，我们建议1) 确定Mer配体对肿瘤分泌的调控机制及其在肿瘤细胞中的表达 人类肿瘤可以预测化疗效果，2)确定哪种形式的化疗效果最好 结合PTP1B抑制的强大免疫激活和3)确定 化疗/PTP1B抑制联合治疗对获得性免疫反应的影响。

PROJECT SUMMARY Despite advances in diagnosis and treatment, cancer is the second leading cause of death in the United States. The discovery and targeting of adaptive immune checkpoints (like PD-1 and CTLA4) has been a boon to cancer patients. Unfortunately, only a subset of patients will respond and those that do often relapse. In an attempt to improve the efficacy of adaptive immune targeted therapy, several clinical trials have been proposed or are underway, exploring the combination of checkpoint blockade with chemotherapy. One rationale for combination therapy is that chemotherapy induces immunogenic tumor cell death which provides robust activation of the anti-tumor response by releasing neo-antigens and Damage Associated Molecular Patterns (DAMPs) that initiate the innate pro-inflammatory response. We discovered and characterized a novel innate immune checkpoint utilized by tumor cells to suppress the immune response during chemotherapy. We found that tumor secreted proteins bind and activate the macrophage Mer receptor, leading to a reduction in the expression of the key Toll-Like Receptor (TLR) adapter protein MyD88. In the absence of MyD88, macrophages are no longer able to respond to DAMP/TLR signaling, effectively preventing the pro-inflammatory response during chemotherapy. This suppressive mechanism is characteristic of tumors of diverse origins including melanoma, lung, pancreas and breast cancers. Our mechanistic studies have identified that ligand-activated macrophage Mer induces ternary complex formation, increasing the association of Mer, Stat1 and a phosphatase known as PTP1b. This complex reduces the phosphorylation and nuclear translocation of Stat1 which leads to a decrease in MyD88 expression. Treating with a PTP1b inhibitor blocks this immune suppressive process and restores DAMP- mediated activation in vitro and in vivo. Combining PTP1b inhibition with chemotherapy causes ~50% decrease in tumor growth in multiple murine cancers, including chemotherapy resistant models. We hypothesize that by targeting the Mer:PTP1b axis, we may be able to improve the innate, and subsequent adaptive, immune response during chemotherapy. To test our hypothesis we propose to 1) determine the regulatory mechanism governing tumor secretion of Mer ligands and whether their expression in human tumors is predictive of chemotherapy response, 2) identify which forms of chemotherapy yield the most robust immune activation in combination with PTP1b inhibition and 3) ascertain the effects of chemotherapy/PTP1b inhibition combination therapy on the adaptive immune response.